A solid pharmaceutical composition or dosage form, such as a tablet or capsule, is generally composed of a mixture of active ingredient(s) and excipient(s). The reproducibility of the adsorption of an active ingredient (drug) from a solid composition form after oral administration depends on several factors such as the release of the drug from the composition and the dissolution or solubilization of the drug under physiological conditions. Because of the critical nature of the release of the drug from the composition and the dissolution or solubilization of the drug, a dissolution test is highly relevant to the prediction of the in-vivo performance of a drug. Drug approving authorities such as the FDA and EMA often require pharmaceutical companies to determine the drug release characteristics of any new pharmaceutical composition in order to obtain approval. These tests can also be required as an USP quality parameter, to assess batch-to-batch quality of a pharmaceutical composition, for accepting products, waiving bioequivalence requirements or supporting requests for other bioequivalence requirements than the recommended.
Various protocols have been developed for conducting the in-vitro dissolution tests and are routinely applied for both product development and quality control. Drug dissolution testing is mostly conducted using recommended compendia methods and apparatus, such as the U.S. Pharmacopoeia and the European Pharmacopoeia e.g. USP 34 <711> and EP 7.2, 2.9.3. Dissolution media typically used in such tests are for example water and buffers such as phosphate buffers or citrate buffers. Different types of dissolution apparatus, based on different stirring methods are available commercially and are recognized by the compendia methods. These apparatus include: paddle, basket, flow-through, and reciprocating cylinder. While exact procedures (protocols) and apparatus vary, all drug dissolution test methods involve placing the pharmaceutical composition or dosage form into a dissolution medium and applying some stirring to the dissolution medium in order to promote disintegration and dissolution of the drug under test.
The dissolution medium and the detection method for determining the amount of the released drug in the dissolution medium depends upon (is chosen according) the chemical nature of the drug, and physical and stability considerations are also of great importance in making the appropriate choices.
The test contained in the pancrelipase Delayed Release Capsule, USP Monograph for the determination of digestive enzymes release from pharmaceutical oral dosage forms, such as pancrelipase delayed released capsules is based on the specific measurement of lipase activity. Such method requires a long analysis time and is affected by several drawbacks. The main drawback is the instability of the marker-lipase in the dissolution medium, more precisely in the enteric stage buffer (pH 6.0) dissolution medium; the extent of lipase degradation needs to be established and a correction factor is then introduced into the dissolution calculation to account for lipase activity loss during the test. Furthermore, the complexity of the method (both in the reagent/substrates preparation and the analytical determination) increases significantly the variability of the results and worsens the intra/inter laboratories results' reproducibility. Moreover, lipase assay has a narrow linearity range (8-16 USP units/mL): this represents a significant limitation since the assay covers only capsule strengths ranging between 6,400 and 12,800 USP UI/capsule and therefore the single unit testing approach cannot be performed. The long analysis time in the current method limits the possibility of using it for determining a multi-point dissolution profile.
There are no method/procedure describing how to overcome these drawbacks for determining the release of digestive enzymes from a solid composition.
The digestive enzymes, such as pancrelipase and other pancreatic enzymes products (PEPs) can be administered to patients suffering from exocrine pancreatic insufficiency (EPI); the administration of digestive enzyme supplements allows patients to more effectively digest their food.
Exocrine pancreatic insufficiency (EPI), of which the FDA estimates that more than 200,000 Americans suffer, involves a physiological disorder wherein individuals are incapabile of properly digesting food due to a lack of digestive enzymes made by their pancreas. That loss of digestive enzymes leads to disorders such as the maldigestion and malabsorption of nutrients, which lead to malnutrition and other consequent undesirable physiological conditions associated therewith. These disorders are common for those suffering from cystic fibrosis (CF) and other conditions compromising the exocrine function of the pancreas, such as pancreatic cancer, pancreatectomy, and pancreatitis. The malnutrition can be life threatening if left untreated, particularly in the case of infants and CF patients, and the disorder can lead to impaired growth, a compromised immune response, and shortened life expectancy.
Digestive enzymes, such as pancrelipase and other pancreatic enzymes products (PEPs), can be administered to at least partially remedy EPI. The administered digestive enzymes provide for patients to be able to more effectively digest their food.
Pancreatic enzymes, which have been used in the treatment of EPI to compensate for lost digestive function, have been in use for more than 60 years. Their use until recently was not subject modern regulatory guidelines governing drug approvals based on safety, and efficacy, and manufacturing controls. Recently, pancreatic enzyme replacement therapies have become the subject of US and European regulatory authority initiatives that require that marketed pancreatic enzyme products to go through the current drug approval process in order to remain in commerce. Zenpep®, Creon® and Pancreaze® are three products that successfully went through the process set by the FDA and are approved for marketing in the United States. In other territories/countries where similar initiatives are still proceeding or have not been implemented as yet, a variety of pancreatic enzyme products are still available.
Capsules containing digestive enzymes such as pancrelipase have been developed for oral administration. However, if a patient is unable to swallow the capsules, each capsule can be opened and the contents sprinkled on a small amount of food, usually a soft, acidic food (such as commercially available applesauce) and administered orally to the patient with a spoon. Alternatively, such medications may be administered orally for infants and children, using a syringe device containing the contents suspended in a medium amenable to administration thereby.
The pancrelipase products are generally labeled as containing three enzyme classes, lipase, amylase, and protease, and the levels or potency of which are listed. These enzymes catalyze the hydrolysis of fats into glycerol and fatty acids, starch into dextrin and sugars, and proteins into amino acids and derived substances. Digestion is, however, a complex process involving many other enzymes and substrates that contribute to correct digestive functioning and producing the full range of digestive products. Other enzymes contained in pancrelipase include trypsin, carboxypeptidases, elastases, phospholipases, and cholesterases amongst others and various co-factors and coenzymes. These substances are produced naturally in the pancreas and also contribute to correct digestive functioning.
Pancrelipase is typically prepared from porcine pancreatic glands, although other sources can also be used, for example those described in U.S. Pat. No. 6,051,220, U.S. 2004/0057944, U.S. 2001/0046493, and WO2006044529, each of which is herein incorporated by reference in its entirety for all purposes.
Pancreatic enzymes show optimal activity under near neutral and slightly alkaline conditions. Under gastric conditions, pancreatic enzymes may be inactivated with a resulting loss in biological activity. Therefore, exogenously administered enzymes are generally protected against gastric inactivation and remain intact during their transit through the stomach and into the duodenum. Therefore, it is desirable to coat pancreatic enzymes. Pancreatic lipases are the most sensitive to gastric inactivation and are key enzymes in the treatment of malabsorption. Lipase activity is typically monitored to determine the stability of an enzyme composition containing lipase. The entire contents of U.S. Pat. No. 7,658,918 issued to Ortenzi et al. is expressly incorporated by reference in its entirety herein for all purposes, and describes stable digestive enzyme compositions and explains that certain particulate medications, administered orally, are designed to pass through the stomach of the patient and thereafter to release within the intestines. The administration of a proper dosage of such particulate medications to patients, particularly infants and children, should be as accurate as possible.
Unfortunately, no process for measuring the amount of digestive enzymes released from a solid pharmaceutical composition or dosage form with good precision and good sensitivity, and that is ready to be implemented in different laboratories has been described.